This application addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic, 01-AA-102*: Functional Roles of Neuroimmune Factors in Mediating Behavior. A critical unanswered challenge in understanding neuroimmunity and adverse behavioral conditions is whether activation of the neuroimmune system can be regulated so as to abrogate or ameliorate the development of neuroinflammation and its biobehavioral consequences. As we have shown and reviewed, IL-1[unreadable]/IL-1RA balance is vital to the development and persistence of biobehavioral complications that occur during activation of the neuroimmune system. We have demonstrated, in mouse models, that increased severity and delayed recovery from neuroimmune activation is due to a failure in IL-1[unreadable] counter-regulation and can be rectified by administration of IL-1RA, the naturally occurring antagonist to IL-1. Importantly, we have shown that IL-4, an essential regulator of T helper 1/T helper 2 (Th1/Th2) balance and inducer of alternative macrophage activation is key to lipopolysaccharide (LPS)-dependent up- regulation of IL-1RA and that IL-4 resistance, which occurs in diseases such as type 2 diabetes, causes failure in appropriate IL-1RA production seriously prolonging biobehavioral recovery from neuroimmune system activation. Thus, the objective of this research project is to determine whether the neuroimmune system can be skewed Th2 protecting it from Th1-driven immune responses. In support of this goal, we have exciting new preliminary data that show mice fed a diet containing 10% soluble fiber are markedly resistant to and recover much faster from LPS-induced social withdrawal, a biobehavior directly tied to brain-based up-regulation of the proinflammatory cytokines IL-1[unreadable], TNFa and IL-6. These soluble fiber-fed mice are skewed Th2, possess peripheral macrophages that are alternatively activated and show a distinct increase in brain IL-4 and IL-1RA. Significantly, IL-4 knockout mice are resistant to the immunobehavioral effects of a soluble fiber diet. These findings are the first to show that a readily available dietary component favorably impacts neuroimmunity and activated-neuroimmune system-associated biobehaviors. The most important question that will be answered by our proposed experiments is: Can soluble dietary fiber be used to block activation of the neuroimmune system and mitigate the biobehavioral consequences of brain-based innate immune activation? Successful completion of this project will identify new targets and potential therapies for alleviating or improving neuroimmune function for a variety of behavioral conditions including those tied to excessive drinking, anxiety and depression. A critical unanswered challenge is determining if neuroinflammation can be prevented or ameliorated. We have developed a novel dietary strategy using soluble fiber that has the potential to block adverse activation of the neuroimmune system and the sickness symptoms associated with brain inflammation. Therefore, a vital and fruitful new area of research is investigating whether the neuroimmune system can be redirected from a proinflammatory state and directed toward an anti-inflammatory state via dietary intervention. Successful completion of our objectives will provide new targets and potential therapies for alleviating or improving a variety of behavioral conditions including those tied to excessive drinking, anxiety and depression.